Hyperglycaemia is a damaging medical condition. Hyperglycaemia wreaks its effects via inappropriate glycation of molecules within cells. This glycation occurs following generation of reactive 1,2-dicarbonyls such as glyoxal and methylglyoxal. These reactive species modify molecules in the cell and cause negative pathology.
Glycation, the non-enzymatic formation of sugar-protein and sugar-nucleotide adducts, plays a major role in disrupting cell function and causing tissue damage in a range of pathologies such as diabetes, aging and neurodegeneration [1-3]. Glycation increases in response to the elevation of glucose that occurs in unregulated diabetes and is a major cause of diabetic complications [4, 5]. Within the cell excessive glucose can lead to molecular damage through the formation of 1,2-dicarbonyl compounds such as methylglyoxal from the triose phosphate intermediates of glycolysis [1, 6] or from the metabolism of acetone generated during ketosis [7]. These reactive 1,2-dicarbonyls often exist in modified chemical forms in situ including reversible hemiacetals, hemithioacetals and hemiaminals with small biomolecules and with reactive moieties on proteins and nucleic acids [8, 9]. In addition they can react directly with free amine functions on proteins and nucleic acids, thereby generating substantial permanent modifications such as arginine-derived hydroimidazolones and lysine cross-links on proteins [10], and guanine-derived imidazopurinones on DNA [11]. Such modifications are thought to result in biochemical dysfunction by altering protein structure and activity, and by inducing genomic mutations [2]. These markers of glycation damage are elevated in many clinical samples from diabetic patients and also in animal models of diabetes and aging [2,4,9,12,13], consistent with a contribution from these reactions to cell damage and pathology. An important role for methylglyoxal and glyoxal in pathology is further supported by the existence of the glyoxalase enzyme system, which specifically degrades these two dicarbonyls [14]. Loss of the glyoxalase degradation pathway renders organisms more susceptible to glycation and subsequent damage while its over-expression increases lifespan in Caenorhabditis elegans [15]. Thus dicarbonyl-associated glycation of proteins and nucleic acids is a significant contributing factor in a range of pathologies, particularly those associated with diabetes or aging.
In hyperglycaemia, there is considerable evidence for mitochondrial damage and elevated oxidative stress that contributes to pathology, and this has been in part ascribed to mitochondrial glycation due to methylglyoxal and glyoxal [16-21]. Furthermore these reactive dicarbonyls disrupt mitochondrial function in vitro [22-24]. Therefore, understanding the contribution from glycation damage by reactive dicarbonyls to mitochondrial dysfunction is important for analyzing and understanding the pathology associated with hyperglycaemia. However, the mechanistic details are uncertain, and it has proven difficult to specifically evaluate the importance of these processes. This is in part due to the uncertainties related to the distribution of methylglyoxal and glyoxal between the cytosol and mitochondria. In known approaches to combating the effects of hyperglycaemia, it has been attempted to use reactive guanidine groups. This forms a generalised “mopping” approach. The guanidine groups react with glyoxal/methylglyoxal groups. However, this guanidine approach is entirely untargeted. This is a drawback in the art.